The human skin consists of two major layers, the bottom thicker layer called the dermis and the top thinner layer called the epidermis. The epidermis is composed principally of three types of cells, the keratinocytes, the melanocytes and the cells of Langerhans. The epidermis cells are generated on the bottom of the epidermis and work their way to the top, where they eventually flake or slough off. This epidermis “turnover” takes approximately 2-4 weeks and often twice as long in people as they age.
The dermis is the layer that provides strength, elasticity and the thickness to the skin, and provides the epidermis with a solid support and is also its nutritive element. The dermis is composed mainly of fibroblasts and of an extracellular matrix itself composed principally of collagen, elastin and a substance called ground substance, which are compounds synthesized by the fibroblasts. The dermis is also composed of leukocytes, mastocytes or tissue macrophages, and blood vessels and nerve fibers pass through it. The dermis contains biologically young cells, including stem cells, which can grow out to form biologically younger skin under appropriate conditions. This possibility underlies many standard treatments in the field of dermatology including the various forms of mechanical, chemical and laser dermabrasion.
With aging, the thickness of the dermal layer is reduced, which is believed to be at least partially responsible for the formation of wrinkles in aging skin. In addition, the decreased rate of cellular turnover in the epidermis results in dull, dry and rough skin. The passage of time is also reflected by a slackening of tissue, a loss of cutaneous elasticity, a leathery or dry appearance and by the yellowing and loss of radiance of the skin. The aging process also results in a reduction in cells and in blood supply, and a flattening in the junction between the dermis and epidermis.
Although controversy exists about the part of the cell that is the “pacemaker” for aging, most scientific opinion favors the mitochondrion, which is also involved in the regulation of the metabolism of free radicals. These compounds, also called “reactive oxygen species” (ROS), are important signals regulating cell metabolism and function in a number of ways, including their actions on the “transcription factors” that are a major mechanism for control of gene expression. Unfortunately, treatment with “free radical quenchers” such as vitamin E or vitamin C or the grape skin ingredient resveratrol, have generally had minimal or no beneficial effects in the relevant age-related conditions, including Alzheimer disease.
Treatments designed to prolong or promote youthful appearance of skin include topical applications of cosmetic preparations, lotions and moisturizers. Many skin care compositions have been created to treat wrinkles and fine lines and restore the youthful appearance of skin, and most of these are intended only to improve the skin's surface characteristics, for example, to minimize environmental effects and stress on the skin, improve texture, firmness and elasticity, counteract dryness, smooth out wrinkles, minimize age spots, improve color, and increase moisture content of the skin. However, none of these focus on the underlying age-related changes in mitochondrial metabolism that underlie alterations in ROS.
Many such skin compositions have been made with different ingredients to promote the health of skin. For example, U.S. Pat. No. 5,686,489 (Yu) discussed methods of treating aging-related skin conditions by topically applying to the skin an alpha hydroxyacid ester, and U.S. Pat. No. 6,328,987 (Marini) discuss improving the appearance of aged or damaged skin by topically applying compositions containing alpha interferon.
Other skin and cosmetic compositions incorporate antioxidants in order to improve the appearance of wrinkled, lined, dry, flaky, aged or photodamaged skin and improve skin thickness, elasticity, flexibility, radiance, glow and plumpness. For example, the compositions disclosed in U.S. Pat. No. 6,270,780 (Carson et al.) and U.S. Pat. No. 6,358,517 (Pillai et al.) incorporate resveratrol as a primary ingredient in addition to a cosmetically acceptable vehicle. Carson et al. combine hydroxyl acid with the resveratrol, and Pillai et al. combine a retinol, namely retinoic acid, retinol or retinyl acetate, with the resveratrol. In addition, U.S. Pat. No. 6,399,046 (Schenrock et al.) discusses the use of catechins or gallic esters of catechins, such as in extracts from green tea, for intensifying natural skin tanning or for stimulating melanogenesis in human skin. While some of these formulations include antioxidants, such as resveratrol, none include chemicals that act to restore mitochondrial function in the skin cells.
In order to survive and work properly, skin cells, like all eukaryotic cells, require energy, which is derived mostly from the diet. Food gets successively digested and metabolized to simple molecular entities that the individual cells, using their mitochondria, can convert into energy. However, because the mitochondrial membranes are permeable only to certain molecules, carbohydrates and certain amino acids have to be broken down in the cytosol into pyruvate, while fatty acids can be absorbed by the mitochondria with the help of a specific carrier, L-carnitine.
During normal operation of the catabolic process in body cells, energy is harvested and subsequently stored in a readily available form, namely, the phosphate bonds of adenosine triphosphate (“ATP”). When energy is required for anabolic processes, a phosphate bond of ATP is broken to yield energy for driving anabolic reactions and adenosine diphosphate (“ADP”) is regenerated. The process of catabolism involves the breakdown of proteins, polysaccharides, and lipids inside the mitochondria. Proteins are broken into smaller peptides and constituent amino acids, polysaccharides and disaccharides are broken down into their monosaccharide constituents, and lipids are broken down into glycerol and the fatty acid constituents. These compounds are further broken down into even smaller compounds, principally, two-carbon acetyl groups.
The two-carbon acetyl group, an essential component in the catabolic process, is introduced into the Krebs tricarboxylic acid cycle (“Krebs cycle”) via acetyl coenzyme A. The acetyl group serves as a carbon source for the final stages of catabolism. The Krebs cycle and an accompanying electron transport system involve a series of enzymatically controlled reactions that enable complete oxidation of the two-carbon acetyl group to form carbon dioxide and water. As is well known, acetyl groups are introduced into the Krebs cycle by bonding to oxaloacetic acid to form citric acid. During subsequent steps of the Krebs cycle, citric acid is converted into aconitic acid and then into isocitric acid. As isocitric acid is converted into ketoglutaric acid, one carbon atom is completely oxidized to carbon dioxide. As ketoglutaric acid is converted into succinic acid, a second carbon atom is completely oxidized to carbon dioxide. During the remaining steps, succinic acid is converted into fumaric acid, fumaric acid is converted into malic acid, and malic acid is converted into oxaloacetic acid. Each complete turn of the Krebs cycle harvests the energy of the acetyl group to yield one molecule of ATP, three molecules of nicotinamide adenine dinucleotide (“NADH”), and one molecule of flavin adenine dinucleotide FADH2. The NADH and FADH2 are subsequently used as electron donors in the electron transport system to yield additional molecules of ATP.
Critically, the electrons (“reducing equivalents”) generated in the Krebs tricarboxylic acid cycle are quantitatively the primary source both of electrons for formation of free radicals and of reducing equivalents to remove (“quench”) free radicals. Thus, facilitation of a normal Krebs cycle is expected to facilitate normalization of free radical (ROS) metabolism and signaling.
The Krebs cycle also generates carbon dioxide (CO2) and electron-transporters NADH and FADH2 that feed the electron transport chain or respiratory chain reducing oxygen (O2) into water (H2O) and generating a proton gradient. This proton gradient creates a natural flow back into the mitochondrial matrix through a protein complex that produces ATP, the principle cellular energy store. For example, ATP is directly used in biochemical synthesis, signal transduction, cell movement, cellular division, and ion pumping.
The Krebs cycle and the accompanying electron transport system occur in the cell mitochondria, which are present in different types of cells in varying numbers depending upon the cellular energy requirements. For example, neuronal and cardiac muscle cells have high numbers of mitochondria because they have extremely high energy requirements. Because of their high energy requirements, these types of cells are particularly vulnerable to a breakdown of the catabolic pathways or otherwise defective intracellular energy metabolism, leading to neurodegenerative disorders or conditions such as Alzheimer's Disease, Parkinson's Disease and Huntington's Disease.
The administration of agents that improve energy metabolism, and possibly prevent cell death, has been suggested for the treatment of disorders characterized by energy-deficient cells. One approach to augmenting the energy level of energy-deficient cells (i.e., as a result of hypoxia or hypoglycemia) involves the administration of pyruvate, which is later converted to acetate during normal metabolism. According to U.S. Pat. No. 5,395,822 (Izumi et al.), the administration of pyruvate to an animal before or after an ischemic event (i.e., which produces a state of hypoxia or hypoglycemia) is sufficient to prevent neuronal degradation that normally is associated with the ischemic event.
In U.S. Pat. No. 6,537,969, which is incorporated herein by reference, the present inventor disclosed a pharmaceutical composition to improve cerebral function in an individual having a disorder involving impaired mitochondrial function, such as age-related conditions, e.g., Alzheimer's Disease, where brain mitochondrial metabolism has been robustly shown to be impaired. That composition was designed to ameliorate the changes in mitochondrial metabolism that are believed to underlie the changes in ROS metabolism and signaling as a treatment for such systemic diseases.
U.S. Pat. No. 6,372,791 (Shapiro et al.) has suggested topically administering carnitine or a therapeutically acceptable salt or ester thereof and pyruvic acid or a therapeutically acceptable salt or ester thereof in order to increase metabolic activity in the skin (e.g., the production of ATP in the skin cells or the increase of mitochondrial activity in the skin cell), promote energy production or the uptake of oxygen into the skin (e.g., increasing the amount of oxygen stored in the skin cells or increasing the rate by which oxygen is taken in by the skin cells), and promote the utilization of oxygen (O2) in the skin (e.g., increasing the amount of oxygen utilized, e.g., converted to CO2 or other compounds, in the skin cells or increasing the rate by which oxygen is utilized by the skin cells).
It is desirable to provide for healthier, “biologically younger” skin, by enhancing skin firmness and elasticity, evening skin tone/texture, making skin more radiant, enhancing skin glow, and enhancing skin barrier function through the administration to the skin of substances that promote the normal mitochondrial activity of the skin cells.
It is desirable to provide a skin care composition that ameliorates the changes in mitochondrial metabolism in skin cells and that restores mitochondrial function to skin cells to make skin “younger”.